Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:12][C:13]1[N:22]=[CH:21][C:20]2[NH:19][CH2:18][C@H:17]3[CH2:23][O:24][CH2:25][CH2:26][N:16]3[C:15]=2[N:14]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.O>[Cl:12][C:13]1[N:22]=[CH:21][C:20]2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:18][C@H:17]3[CH2:23][O:24][CH2:25][CH2:26][N:16]3[C:15]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1ncc2c(n1)N1CCOC[C@@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C[C@H]2COCCN2c2nc(Cl)ncc21
Yield: 55.2 %

Procedure:
Potassium tert-butoxide in tert-BuOH (1M, 2.65 mL, 2.65 mmol) was added to a solution of (S)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x4, 500 mg, 2.206 mmol) in DMF (5 mL) at 0° C. The resultant mixture was stirred at room temperature for 30 minutes. tert-Butyl 2-bromoacetate (0.421 mL, 2.87 mmol) was added to the reaction mixture at 0° C. The resultant mixture was stirred at room temperature for 1 hour. After addition of water, the resultant mixture was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (gradient 20-80% EtOAc/hexane) to afford the title compound as an off-white solid (415 mg, 55.2%). 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.00-3.10 (m, 1H), 3.15-3.28 (m, 2H), 3.37 (dd, J=11.37, 8.84 Hz, 1H), 3.52-3.62 (m, 1H), 3.64-3.75 (m, 2H), 3.86-4.06 (m, 3H), 4.52 (dd, J=13.77, 1.89 Hz, 1H), 7.22 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O3, 341.14. found 341.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:19]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyridin-3-yl-benzaldehyde, of Preparation 23, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, 1H), 8.56 (m, 1H), 7.85 (m, 1H), 7.53 (d, 2H), 7.45 (d, 2H), 7.34 (m, 1H), 7.24 (m, 1H), 6.96 (m, 2H), 6.78 (dd, 1H), 4.51 (s, 2H), 3.84 (s, 2H), 3.80 (s, 2H), 1.47 (s, 9H); MS 405 (M+1).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.O=O>[Cu].C(O)C>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)CC1
Agent: [Cu]
Agent: O=O
Solvent: c1ccncc1
Solvent: CCO
Product: Nc1ccn(-c2ccccc2)n1
Reaction time: 2 h

Procedure:
1-phenyl-3-amino-2-pyrazoline, copper salt (CuCl) and metallic copper, if any, and/or pyridine, in the form of a suspension or of a solution in the solvent (e.g., ethyl alcohol) are introduced, in the desired amounts (between 5 and 6%), into a reactor equipped with feeding systems for reagents and with an effective stirrer. Stirring is started in an oxygen atmosphere. After about 2 hours, oxidation is concluded and the whole solid is dissolved. The catalyst is filtered, the solvent is distilled under vacuum, and the 1-phenyl-3-aminopyrazole is isolated by extraction with, e.g., n-heptane. Additional 1-phenyl-3-aminopyrazole is recovered by treating the n-heptane extraction residue with diluted hydrochloric acid, followed by neutralization with aqueous NaOH to precipitate the 1-phenyl-3-aminopyrazole. Optionally, the heptane extraction residue diluted with hydrochloric acid can be clarified with animal charcoal, prior to neutralization thereof. As is known, the 1-phenyl-3-aminopyrazoles are an important class of products which are valuable for various industrial uses, such as active intermediates in the preparation of dyestuffs, of sensitive agents for use in photography, and of other fine chemicals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:40][CH:41]([CH3:46])[C:42]([O:44][CH3:45])=[O:43]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:40][CH:41]([CH3:46])[C:42]([O:44][CH3:45])=[O:43])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)C(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)C(C)NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.10 g (19.1 mmol) 5-chloro-thiophene-2-carboxylic acid are combined with 4.44 ml (40 mmol) NMM and 6.42 g (20 mmol) TBTU in 50 ml THF and then stirred for 2 hours under a nitrogen atmosphere at ambient temperature. Then 2.79 g (20 mmol) methyl 2-aminopropionate-hydrochloride and 50 ml THF are added and the mixture is stirred for a further 16 hours at ambient temperature. Then the reaction mixture is poured into water, extracted with ethyl acetate, the combined organic phases are washed with sat. sodium hydrogen carbonate solution, water, 0.5-molar hydrochloric acid, water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down completely i. vac.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH2:11][CH3:12])[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]1[CH3:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:11]([N:9]1[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([CH3:18])[CH:4]([CH2:3][CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:10]1)[CH3:12]
Reactant: C1COCCN1
Reactant: CCN1CC(CCCl)N(C)c2ccccc2C1=O
Product: CCN1CC(CCN2CCOCC2)N(C)c2ccccc2C1=O
Yield: 61 %

Procedure:
A solution of 30 g (0.112 mole) of 2-(2-chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one in 70 ml of morpholine was refluxed for 3 hrs, concentrated on the rotary evaporator and the residue partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over anhydrous sodium sulfate and concentrated on the rotary evaporator. The residue was crystallized twice from isopropyl ether containing a small amount of ethanol, m.p. 128°-148° C. Recrystallization from toluene gave 19.5 g (61%) of product, m.p. 128°-148° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[OH-].[Na+:32].CC(C)=O>CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:32]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 60.1 %

Procedure:
Fluvastatin (3 g) was completely dissolved in MeOH (15 ml) at reflux temperature. Then, the solution was filtered to obtain a clear solution and heated to reflux again. NaOH (s) (0.29 g) was added at reflux temperature to obtain a precipitate. The slurry was cooled to room temperature to obtain a paste-like mixture. Acetone (30 g) was added dropwise at room temperature and the solution stirred at room temperature for 21 h to obtain a massive precipitate. The product was filtered under nitrogen flow, washed with acetone (2×15 ml) and dried at 50° C. in a vacuum oven for 22.5 h to obtain 1.89 g (62%) of fluvastatin sodium Form XLVIII.
Reaction SMILES: CS([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34]>CN(C)C(=O)C>[CH3:23][NH:22][C:20]([C:16]1[CH:15]=[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:7]3[N:8]=[C:4]([NH:24][C@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][C@H:26]4[OH:34])[O:5][C:6]=3[CH:12]=2)[CH:19]=[CH:18][N:17]=1)=[O:21]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4c5ccccc5C[C@H]4O)oc3c2)ccn1

Procedure:
A solution of 4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide (17 mg, 0.05 mmol, 1.0 eq) and (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (30 mg, 0.2 mml, 4.0 eq) in 1 mL of N,N-dimethylacetamide was heated in the microwave at 90° C. for 600 seconds. The crude product was purified by reverse phase prep HPLC to give the title compound. MH==417.0.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CN(C=O)C.C(N(CC)CC)C.[F:23][C:24]1[CH:41]=[CH:40][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C(OCC)(=O)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][S:36]([C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:27]2[CH:40]=[CH:41][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:31][CH:32]=1)(=[O:37])=[O:38])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of glycine tert butyl ester hydrochloride salt (5.9 g, 18 mmol) and DMF (20 mL) at 0° C. was added triethylamine (6.5 mL, 45 mmol) and 4-(4-fluoro-benzyloxy)-benzenesulfonyl chloride. After stirring for 1 h, the mixture was warmed to room temperature and stirred for an additional hour. The mixture was diluted with ethyl acetate, washed with 1M HCl, saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with ether-hexane afforded 10.8 g of [4-(4-fluoro-benzyloxy)-benzenesulfonylamino]-acetic acid tert-butyl ester as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17]CC2C=CC=CC=2)=O)[CH2:11][CH2:10]1.N1CCCCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][CH2:51][CH2:52]C(O)=O>CN(C=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[O:17])[CH2:52][CH2:51][CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)[CH2:13][CH2:14]1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ncccn2)CC1
Reactant: O=C(O)CCCc1cccs1
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CCCc1cccs1)N1CCC(CNc2ncccn2)CC1
Reaction time: 2 h

Procedure:
Benzyl 4-[(2-pyrimidinylamino)methyl]-1-piperidinecarboxylate (EXAMPLE 16) was hydrogenated as described in EXAMPLE 30, Step 1. The resulting piperidine was combined with EDC (1.3 equiv.), HOBT (1.0 equiv.), and 4-thiophen-2-yl-butyric acid (1.0 equiv.) in DMF and stirred for 2 h. The resulting reaction solution was partitioned into ethyl acetate and aqueous sodium bicarbonate. The organic layer was seperated and washed with pH 4.5 citric acid buffer (10% citric acid and sodium hydroxide), dried (sodium sulfate), and concentrated to yield the desired 1-[4-(pyrimidin-2-ylaminomethyl)-piperidin-1-yl]-4-thiophen-2-yl-butan-1-one. M.S. (M+1): 345.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCCc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoronitrobenzene (500 mg, 2.27 mmol), 2-(3-fluorophenyl)ethylamine (411 mg, 2.95 mmol), and potassium carbonate (1.0 g, 7.24 mmol) in 7 mL N,N-dimethylformamide was heated at 80° C. for 1 hour. The mixture was diluted with ethyl acetate, rinsed with brine (three times), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: NCCCCO
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(NCCCCO)c1ccc2c(c1)OCO2
Yield: 75 %

Procedure:
1,3-Benzodioxole -5-carboxylic acid (2.0 g, 12.0 mmol) and 4-amino-1-butanol (1.4 ml, 15.6 mmol) were coupled according to the procedure of Example 17 to 2.1 g (75% yield) of a pale yellow solid. MP 95-98° C.; 1H N (DMSO-d6): δ1.38-1.65 (m, CH2, CH2), 3.31 (q, CH2), 3.39 (q, CH2), 4.39 (t, NH), 6.08 (s, CH2), 6.98 (d, 1 Ar H), 7.37 (d, 1 Ar H), 7.4 (d-d, 1 Ar H), 8.27 (t, NH) Electrospray Mass Spec: m/z 238.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:21]=2)[C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=2)=[N:8][CH:9]=1)[CH3:3].S(O)(C(F)(F)F)(=O)=O.FC(C(O)=O)(F)F.[OH-].[Na+]>>[NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH2:27])[N:21]=2)[C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=2)=[N:8][CH:9]=1)[CH3:3]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)N)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a 25 mL round-bottomed flask was added 4-(5-(1-aminoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (150 mg, 0.246 mmol) and 7% TfOH-TFA (5 mL).The solution was heated at 70° C. for 20 minutes. The mixture was cooled to 0° C. and neutralized with 10N NaOH. The obtained suspension was filtered to provide 4-(5-(1-aminoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (80 mg, 88% yield) as a yellow solid. m/z (ESI positive ion): 371 (M+H)+. 1H NMR 400 MHz, DMSO-d6): δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.26 Hz, 3H) 1.75 (br s, 2H) 2.23 (s, 3H) 3.81-3.86 (m, 1H) 7.60 (d, J=61.62 Hz, 2H) 8.09-8.25 (m, 3H) 8.61 (s, 1H) 11.68 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[C:7]([C:9]1[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=1)#[N:8].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CN(C)C=O>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[CH:14]=[C:9]([C:7]#[N:8])[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: ClCCCCBr
Reactant: N#Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to a solution of 2.06 g (15.0 mmol) of 5-cyanouracil in 50 ml of dimethyl sulfoxide (DMSO) and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C., and 2.07 g (15.0 mmol) of K2CO3 were added in portions over the course of 1 hour. The mixture was then stirred at 20° C. for 10 minutes (dialkylated product already identifiable). Water was added to the reaction mixture, and then the aqueous mixture was extracted twice with diethyl ether and twice with methylene chloride. The aqueous phase was adjusted to pH 3-4 and then extracted with methylene chloride. The methylene chloride phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 0.6 g. 1-(4-Chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile was employed without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>>[Br-:7].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][N+:4]2[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: Cn1ccnc1
Reactant: COc1ccc(CCCBr)cc1
Product: COc1ccc(CCC[n+]2ccn(C)c2)cc1
Product: [Br-]
Temperature: 140 °C

Procedure:
A mixture of 2.50 g (0.03 mole) of 1-methyl-1H-imidazole and 6.9 g (0.03 mole) of 1-(3-bromopropyl)-4-methoxybenzene is heated at 140° C. for 1.5 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (methanol:1M sodium chloride, 95:5). At the completion, the cooled reaction product is triturated thoroughly with ether and on drying, provides the title compound.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCCc1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
67.1 mg (0.50 mmol) of 3-phenyl-2-propen-1-ol (34), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 6 hours at 800 rpm (reversed every 30 minutes). After the lapse of 6 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 64.7 mg (0.475 mmol) of 3-phenyl-1-propanol (35). The yield was 95%. The reaction is expressed by the following scheme.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[O:27]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[CH2:37][CH2:38][NH2:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:39][CH2:38][CH2:37][C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:35]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Oc5ccccc5)c4)cc3)c(Cl)cc21
Reaction time: 24 h
Yield: 91.2 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (51.6 mg, 0.137 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 3-phenoxyphenethylamine (32.1 mg, 0.151 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.5 mg, 0.164 mmol), and 1-hydroxy-7-azabenzotriazole (5.59 mg, 0.0411 mmol) at ambient temperature. After 24 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (71.6 mg, 0.125 mmol, 91.4% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:21](=[CH:22][CH:23]=2)[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:6][C:5]3=[O:24])[CH:28]=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate (1 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (682 mg) were dissolved in dioxane in a nitrogen atmosphere, and aqueous 2 M sodium carbonate solution (3.8 mL) and tetrakis(triphenylphosphine)palladium (144 mg) were added thereto, and degassed. The reaction liquid was stirred overnight at 100° C., cooled to room temperature, then water was added thereto, and filtered through Celite. The filtrate was extracted with chloroform, and the organic layer was dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 0/100) to obtain the intended product as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.CI>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:15][CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(O)ccc1OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1nc(OC)ccc1OCc1ccccc1
Yield: 48.3 %

Procedure:
Methyl 3-benzyloxy-6-hydroxy-picolinate (0.55 g) was dissolved in 55 ml of acetone and 20 ml of methyl iodide. Potassium carbonate (1.4 g) was added to the solution, and the mixture was refluxed for 3 hr. After cooling, the reaction solution was neutralized with 1 N hydrochloric acid, and was concentrated under the reduced pressure. Methylene chloride and water were then added to the concentrate to conduct extraction. The organic layer was dried over magnesium sulfate, and the dried organic layer was then concentrated under the reduced pressure. The residue was purified by column chromatography (chloroform-methanol) to give 0.28 g (yield 49%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][C:31]=4[F:32])[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][C:31]=4[F:32])[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4cc5cccnc5cc4F)c3n2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4cc5cccnc5cc4F)c3n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
To a solution of Example 131 (0.185 g, 0.412 mmol) in methanol (2 ml), lithium hydroxide (0.161 g, 3.84 mmol) in water (2 ml), THF (4 ml) were added and stirred at RT. After 12 h, pH was adjusted to ca.7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale brown solid (0.150 g, 84%).